Connection and conflict: influence of the hidden curriculum on veterinary residents' professional identities within the specialty of laboratory animal medicine.
To explore the role of the hidden curriculum in residents' development of professional identity during postgraduate training in laboratory animal medicine. 24 residents enrolled in 1 of 7 laboratory animal medicine training programs in the eastern US. 24 qualitative, semistructured interviews were conducted and recorded. Deidentified transcriptions were analyzed by each author using open and axial coding. Constant comparative methodology was used to develop themes and subthemes. Member checks were performed to verify trustability of the conclusions drawn. 3 themes and their related subthemes emerged from the qualitative analysis: 1) building relationships through competent communication (building rapport, practicing clinical empathy, overcoming language barriers, communicating in the "authorized" way, and navigating email limitations), 2) tension within the process of identity formation (acting as the middleman among stakeholders, overcoming the stigma of the policing role, experiencing a lack of power to impact change, and managing a culture of conditional value of veterinary knowledge), and 3) outlets for tension in identity formation (reliance on residency mates, limitations of venting). Our findings suggest that residents are navigating professional identity formation under challenging circumstances that include conflicting stakeholder needs, conditional value of veterinary knowledge, and lack of power to influence change. Residents have limited outlets for relieving the discord between their ideal professional role and their lived experiences. These results provide an important background for refining curricula and creating effective support systems for residents.


[Two-dimensional electrophoretic analysis of the protein spectrum of human brain structures in schizophrenia and senile dementia of the Alzheimer type].
Analysis was made of the composition of four structures of human brain in health (n-12), schizophrenia (n-10), and Alzheimer's senile dementia (n-8). Protein maps obtained by means of two-dimensional electrophoresis were used to analyze tissue samples of the structures under study. In the investigation, the neocortex was represented by the frontal cortex (field 10), the old cortex by the hippocamp, the midbrain by black substance, and medulla oblongata by the inferior olive. Comparative study of the protein maps revealed quantitative differences in certain brain structures in health as well as differences between these structures in health and mental pathology.


Factor Analysis of the DePaul Symptom Questionnaire: Identifying Core Domains.
The present study attempted to identify critical symptom domains of individuals with Myalgic Encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Using patient and control samples collected in the United States, Great Britain, and Norway, exploratory factor analysis (EFA) was used to establish the underlying factor structure of ME and CFS symptoms. The EFA suggested a four-factor solution: post-exertional malaise, cognitive dysfunction, sleep difficulties, and a combined factor consisting of neuroendocrine, autonomic, and immune dysfunction symptoms. The use of empirical methods could help better understand the fundamental symptom domains of this illness.


Functional Gastrointestinal Disorders Common Among Nurses With Poor Sleep Quality in Shanghai, China: A Pilot Study.
This study aimed to determine whether functional gastrointestinal disorders are more common among nurses with self-reported poor sleep. In total, 468 nurses working the day shift or rotating shifts completed two questionnaires: the questionnaire for irritable bowel syndrome (IBS) using Rome III criteria and the Pittsburgh Sleep Quality Index (PSQI). The prevalence of poor sleep was 41.04% (95% confidence interval, CI: [36.23, 45.85]), and poor sleep was significantly more common among rotating-shift nurses than among day-shift nurses (50.70% vs. 29.95%; p < .05). Among nurses with poor sleep, the prevalence of IBS and functional constipation was 35.15% (95% CI: [27.86, 42.44]) and 11.52% (95% CI: [6.65, 16.39]), respectively. After adjusting for age, work schedule, night pain, and psychological factors, IBS (odds ratio, OR: 1.88; 95% CI: [1.03, 2.49]) and functional constipation (OR: 1.77; 95% CI: [0.64, 2.57]) were significantly more common in nurses with poor sleep. We conclude that IBS and functional constipation are prevalent in nurses with poor sleep. Poor sleep was independently associated with IBS and functional constipation among nurses in Shanghai, China.


Distribution of pericentriolar material in multipolar spindles induced by colcemid treatment in Chinese hamster ovary cells.
Mitotic Chinese hamster ovary cells were obtained by treatment with microtubule drugs under various conditions, and the shape of spindles was analysed by phase-contrast microscopy of isolated spindles, and by indirect immunofluorescence staining of whole mitotic cells with anti-tubulin antibody. Bipolarity of spindles was maintained after treatment with 0.05 microM of colcemid for 3.5 h, but increased exposure to higher concentrations (0.32 microM) and for longer durations (5.5 h) led to a marked rise in multipolar spindles. Nocodazole treatment, on the other hand, failed to show a multiplicity of spindle poles even at 3.3 microM. Each pole of a multipolar spindle was associated with pericentriolar material, as shown by staining with an autoimmune serum specific for pericentriolar material. The number of locations with free pericentriolar material capable of polymerizing microtubules in vitro also increased with increasing numbers of spindle poles, suggesting that dispersion of the pericentriolar material resulted in the production of many microtubule-nucleating sites in multipolar spindles. The different efficiencies of recovery from different drugs, which have been known to be quite variable, may be partly due to the different extent of dispersion of the pericentriolar material.


Shifts in bovine CD4+ subpopulations increase T-helper-2 compared with T-helper-1 effector cells during the postpartum period.
This study determined the cytokine profile of CD4+ T-helper cells to elucidate the specific CD4+ T-helper phenotype during the postpartum period. Peripheral blood mononuclear cells were isolated from cows during periods of increased susceptibility (3 d postpartum, n = 7) and decreased susceptibility (mid- to late lactation, n = 6) to mastitis. Isolated mononuclear cells were magnetically separated into CD4(+)-enriched or CD4(+)-depleted populations using specific bovine monoclonal antibodies and were confirmed to be enriched or depleted by flow cytometric analysis. T-helper-1 and T-helper-2 subpopulations were distinguished by cytokine profiles, at both the molecular and protein level, by competitive quantitative reverse transcriptase-polymerase chain reaction and specific bioassays, respectively. The CD4(+)-enriched cultures isolated postpartum had enhanced interleukin-4 and interleukin-10 mRNA transcript expression; cultures isolated during the mid- to late lactating period had enhanced interleukin-2 mRNA transcripts. Depletion of CD4+ lymphocytes decreased, and enrichment of CD4+ lymphocytes increased interferon-gamma transcripts in cultures isolated from mid- to late lactation cows. Interferon-gamma and interleukin-2 bioassays revealed that cytokine secretion paralleled mRNA transcript levels. These data suggest that CD4+ lymphocytes act predominantly as T-helper-2 compared with T-helper-1 within 3 d after calving. Alterations in the T-helper-1 and T-helper-2 responses, and therefore the repertoire of cytokines produced, may be an underlying reason for diminished host immune response during the postpartum period.


Plants mentioned in the Islamic Scriptures (Holy Qur'ân and Ahadith): Traditional uses and medicinal importance in contemporary times.
Over the past thousand years, Islamic physicians have collected cultural, philosophical, sociological and historical backgrounds for understanding diseases and medications. The Prophet Mohammed (Peace Be Upon Him (PBUH) said: "There is no disease that Allah has created, except that Allah also has created its cure." Therefore, Islamic scholars are encouraged to explore and use both traditional and modern forms of medicine. (1) To identify some of the medicinal plants mentioned in the Holy Qur'ân and Ahadith textbooks of the period 700-1500 AD; (2) to compare them with presently used traditional medicines; (3) to evaluate their value based on modern research; and (4) to investigate the contributions of Islamic scholars to the development of the scientific branches, particularly medicine. A literature search was performed relating to 12 medicinal plants mentioned in the Holy Qur'ân and Ahadith using textbooks, Al-Azhar scholars, published articles, the plant list website (http://www.theplantlist.org/), the medicinal plant names services website (http://mpns.kew.org/mpns-portal/) and web databases (PubMed, Science Direct, and Google Scholar). The Islamic Golden Age was a step towards modern medicine, with unique insights and multi-disciplinary aspects. Traditional Islamic Medicine has had a significant impact on the development of various medical, scientific and educational activities. Innumerable Muslim and non-Muslim physicians have built on the strong foundation of Traditional Islamic Medicine by translating the described natural remedies and effects. The influences of different ancient cultures on the traditional uses of natural products were also documented in Islamic Scriptures in the last part of the second millennium. The divine teachings of Islam combine natural and practical healing and incorporate inherited science and technology. In this review, we discuss Traditional Islamic Medicine with reference to both medical recommendations mentioned in the Holy Qur'ân and Prophetic Traditional Medicine (al-Tibb al-Nabawi). Although the molecular mechanisms and functions of some of the listed medicinal plants and their derivatives have been intensively studied, some traditional remedies have yet to be translated into clinical applications.


A rare potentially treatable cause of bilateral optic disc swelling.
Rapid onset bilateral optic disc swelling generally indicates an intracranial problem-that is, papilloedema. However, when there is also visual loss, disease affecting the optic nerves themselves must be considered. We present the diagnostic problem of a patient with optic disc swelling and progressive visual loss. Investigations finally revealed hypocalcaemia secondary to primary hypoparathyroidism. With treatment a marked improvement in vision occurred. This reversible rare cause of optic disc swelling should not be forgotten.


Geometric Calibration Using Line Fiducials for Cone-Beam CT with General, Non-Circular Source-Detector Trajectories.
Traditional BB-based geometric calibration methods for cone-beam CT (CBCT) rely strongly on foreknowledge of the scan trajectory shape. This is a hindrance to the implementation of variable trajectory CBCT systems, normally requiring a dedicated calibration phantom or software algorithm for every scan orbit of interest. A more flexible method of calibration is proposed here that accommodates multiple orbit types - including strongly noncircular trajectories - with a single phantom and software routine. The proposed method uses a calibration phantom consisting of multiple line-shaped wire segments. Geometric models relating the 3D line equations of the wires to the 2D line equations of their projections are used as the basis for system geometry estimation. This method was tested using a mobile C-arm CT system and comparisons were made to standard BB-based calibrations. Simulation studies were also conducted using a sinusoid-on-sphere orbit. Calibration performance was quantified in terms of Point Spread Function (PSF) width and back projection error. Visual image quality was assessed with respect to spatial resolution in trabecular bone in an anthropomorphic head phantom. The wire-based calibration method performed equal to or better than BB-based calibrations in all evaluated metrics. For the sinusoidal scans, the method provided reliable calibration, validating its application to non-circular trajectories. Furthermore, the ability to improve image quality using non-circular orbits in conjunction with this calibration method was demonstrated. The proposed method has been shown feasible for conventional circular CBCT scans and offers a promising tool for non-circular scan orbits that can improve image quality, reduce dose, and extend field of view.


Learning in Volatile Environments With the Bayes Factor Surprise.
Surprise-based learning allows agents to rapidly adapt to nonstationary stochastic environments characterized by sudden changes. We show that exact Bayesian inference in a hierarchical model gives rise to a surprise-modulated trade-off between forgetting old observations and integrating them with the new ones. The modulation depends on a probability ratio, which we call the Bayes Factor Surprise, that tests the prior belief against the current belief. We demonstrate that in several existing approximate algorithms, the Bayes Factor Surprise modulates the rate of adaptation to new observations. We derive three novel surprise-based algorithms, one in the family of particle filters, one in the family of variational learning, and one in the family of message passing, that have constant scaling in observation sequence length and particularly simple update dynamics for any distribution in the exponential family. Empirical results show that these surprise-based algorithms estimate parameters better than alternative approximate approaches and reach levels of performance comparable to computationally more expensive algorithms. The Bayes Factor Surprise is related to but different from the Shannon Surprise. In two hypothetical experiments, we make testable predictions for physiological indicators that dissociate the Bayes Factor Surprise from the Shannon Surprise. The theoretical insight of casting various approaches as surprise-based learning, as well as the proposed online algorithms, may be applied to the analysis of animal and human behavior and to reinforcement learning in nonstationary environments.


New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAFV600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study.
A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC50 = 9-16 μM compared to tamoxifen (IC50 = 27.9 μM). and showed good inhibitory activity against HEP-3B with IC50 = 4.5-14 μM compared to sorafenib (IC50 = 3.5 μM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC50 = 5.3-13.7 μM compared to 5-FU with IC50 = 4.8 μM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC50 = 3-4.5 μM compared to 5-FU with IC50 = 6 μM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC50 of 22.40, 23.20, 22.70, 30.30 μM), EGFR (IC50 of 0.112, 0.205, 0.169 and 0.066 μM) and B-RAFV600E (IC50 of 0.09, 0.06, 0.07 and 0.05 μM).


Non-invasive endothelial function assessment in patients with neurofibromatosis type 1: a cross-sectional study.
Neurofibromatosis type 1 (NF1) is a multi-systemic disease caused by neurofibromin deficiency. The reduced life expectancy of patients with NF1 has been attributed to NF1-associated malignant neoplasms. However, an analysis of death certificates in the USA suggests that vascular disease could be an important cause of early death among these patients. Endothelial dysfunction (ED) is related to vasculopathy and is an early marker of subclinical atherosclerosis. Since neurofibromin has already been demonstrated to affect endothelial cell function, ED may be associated with NF1. The purpose of this study was to assess endothelial function in patients with NF1 using a non-invasive method. NF1 patients and healthy control subjects, aged 18 to 35 years, were included. Subjects were excluded if they had any risk factor for vascular disease or any other condition known to affect endothelial function. Endothelial function was assessed using reactive hyperemia-peripheral arterial tone (RH-PAT) technology. ED was defined as a reactive hyperemia index (RHI) lower than 1.35. Four of the 29 (13.8%) NF1 patients and 1 of the 30 (3.3%) healthy volunteers had ED (p=0.153). RHI medians and interquartile intervals were 1.8 (1.58-2.43) for the NF1 group and 2.02 (1.74-2.49) for the control group (p=0.361). The prevalence of ED was similar in NF1 patients and healthy controls.


ε-Poly-l-lysine-hydroxyphenyl propionic acid/IL-4 composite hydrogels with inflammation regulation and antibacterial activity for improving integration stability of soft tissues and orthopedic implants.
The failure of orthopedic implants is usually caused by inflammation, poor tissue integration, and infection, which can lead to pain, limited mobility, dysfunction of patients. This may require additional surgical interventions, such as removal, replacement, or repair of implants, as well as related treatment measures such as antibiotic therapy, physical therapy. Here, an injectable hydrogel carrier was developed for the steady release of inflammatory regulators to reduce the surface tissue inflammatory response of orthopedic implants and induce soft tissue regeneration, ultimately achieving the promotion of implants stability. The hydrogels carrier was prepared by hydroxyphenyl propionic acid-modified ε-Poly-l-lysine (EPA), hydrogen peroxide and horseradish peroxidase, which showed antibacterial bioactive and stable factor release ability. Due to the introduction of IL-4, EPA@IL-4 hydrogels showed good inflammatory regulation. EPA@IL-4 hydrogels regulated the differentiation of macrophages into M2 in inflammatory environment in vitro, and promoted endothelial cells to show a more obvious trend of tube formation. The composite hydrogels reduced the inflammation on the surface of the implants in vivo, induced local endothelial cell angiogenesis, and had more collagen deposition and new granulation tissue. Therefore, EPA hydrogels based on IL-4 release are promising candidates for promoting of implants surface anti-inflammatory, soft tissue regeneration, and anti-infection.


A cost-minimization analysis of alternative strategies in diagnosing pancreatic cancer.
Several modalities currently exist for tissue confirmation of suspected pancreatic cancer prior to therapy. Since there is a paucity of cost-minimization studies comparing these different biopsy modalities, we analyzed costs and examined effectiveness of four alternative strategies for diagnosing pancreatic cancer. A decision analysis model of patients with suspected pancreatic cancer was constructed. We analyzed costs, failure rate, testing characteristics, and complication rates of four commonly employed diagnostic modalities: 1) computerized tomography or ultrasound-guided fine-needle aspiration (CT/US-FNA), 2) endoscopic retrograde cholangiopancreatography with brushings (ERCP-B), 3) Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNA), and 4) laparoscopic surgical biopsy. If the first attempt with a particular modality failed, a different modality was employed to identify the most preferable secondary biopsy strategy. This analysis identifies EUS-FNA as the preferred initial modality for the diagnosis of pancreatic cancer. Resultant expected costs and strategies in decreasing optimality include: 1) EUS-FNA (1,405 dollars), 2) ERCP-B (1,432 dollars), 3) CT/US-FNA (3,682 dollars), and 4) surgery (17,711 dollars). If a patient presents with obstructive jaundice, decision analysis modeling resulted in a total expected costs of 1,970 dollars if ERCP-B is successful at the time of biliary stent placement. Additional analyses to identify the preferred follow-up modality after a failed alternative method showed that EUS-FNA is the preferred secondary modality if any of the other three modalities failed first, in both the setting of and absence of obstructive jaundice. One- and two-way sensitivity analysis of the variables shows unchanged results over an acceptable range. This cost-minimization study illustrates that EUS-FNA is the best initial and the preferred secondary alternative method for the diagnosis of suspected pancreatic cancer. In addition to local expertise and availability, costs and diagnostic yield should be considered when choosing an optimal diagnostic strategy.


Range-wide assessment of the impact of China's nature reserves on giant panda habitat quality.
Protected areas (PAs) form the backbone of global conservation efforts. Although many studies have evaluated the impact of PAs on land cover, human disturbances, and people's welfare, PAs' impact on wildlife habitat quality remains poorly understood. By integrating wildlife habitat mapping and information of 2183 rural households, we assessed the impacts of nature reserves (a type of PAs) across the entire geographic range of giant pandas (Ailuropoda melanoleuca) on panda habitat suitability change between 2001 and 2013 using the matching approach. We found the impact of nature reserves is concentrated in areas susceptible to human pressure, where 65% of the habitat suitability increase is attributable to the nature reserves' protection. The impact of nature reserves has spilled over to nearby unprotected areas and enhanced habitat suitability there. Nature reserves supported by the central government showed higher performance in improving habitat suitability than their counterparts supported by local governments. Older nature reserves perform better than those established more recently. Our results also show that local households' participation in tourism and labor migration (people temporarily leaving to work in cities) enhanced the ability of nature reserves to improve habitat suitability. These results and methods provide valuable information and tools to support effective management of PAs to enhance the habitat quality of giant pandas and other wildlife species in China and elsewhere.


Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin.
A mucin molecule, which has a molecular weight of greater than 400,000 and which carries tumor associated epitopes recognized by monoclonal antibodies HMFG-1 and HMFG-2, has been purified from human skimmed milk by affinity chromatography followed by passage through a size exclusion column. While treatment of the mucin with hydrogen fluoride for 1 h at 4 degrees C removed the peripheral oligosaccharides, treatment with HF for 3 h at room temperature removed all of its lectin binding ability and revealed a dominant polypeptide of about 68,000. This appears to be the size of the mucin core protein. Monoclonal antibodies have been developed that react with the stripped and partially stripped molecule but not with the intact mucin. From the initial screening on histological sections one of these antibodies, SM-3, reacts with 91% of breast carcinomas but shows little or no reactivity on benign mammary tumors, normal resting, pregnant, or lactating breast. It appears that this monoclonal antibody is reacting with an epitope that is usually masked by oligosaccharide moieties in normal cells but which is exposed, perhaps due to aberrant glycosylation, in malignant cells.


[The role of chronically disordered duodenal patency in the development of post-gastroresection syndrome].
We assessed results of examination and treatment of 100 patients with ulcer disease who had undergone Bilroth-1 stomach resection. Chronic disorder of duodenal patency was revealed in 86% of the patients. This condition was shown to play the leading role in the development of post-gastric resection syndrome. Reflux-gastritis was associated with damping syndrome in 66.3% of the patients and with recurrent ulcer in 8.1%. It is concluded that conservative and surgical treatment of post-gastric resection syndrome should be aimed at correction of chronic disorders of duodenal patency.


Gold-sputtered microelectrodes with built-in gold reference and counter electrodes for electrochemical DNA detection.
Gold-sputtered microelectrodes with built-in gold reference and counter electrodes represent a promising platform for the development of disposable DNA sensors. Pretreating gold electrode surfaces and immobilization of DNA thereon is commonly employed in biosensing applications. However, with no scientific or practical guidelines to prepare a DNA sensor using these miniature gold-sputtered microelectrodes, cleaning and immobilization steps need to be systematically optimized and updated. In this work, we present efficient cleaning and modification of miniaturized gold-sputtered microelectrodes with thiolated DNA probes for DNA detection. Additional discussions on subtleties and nuances involved at each stage of pretreating and modifying gold-sputtered microelectrodes are included to present a robust, well-founded protocol. It was evident that the insights on cleaning polycrystalline gold disk electrodes with a benchmark electrode surface for DNA sensors, cannot be transferred to clean these miniature gold-sputtered microelectrodes. Therefore, a comparison between five different cleaning protocols was made to find the optimal one for gold-sputtered microelectrodes. Additionally, two principally different immobilization techniques for gold-sputtered microelectrode modification with thiolated ssDNA were compared i.e., immobilization through passive chemisorption and potential perturbation were compared in terms of thiol-specific attachment and thiol-unspecific adsorption through nitrogenous bases. The hybridization performance of these prepared electrodes was characterized by their sensitive complementary DNA capturing ability, detected by a standard alkaline phosphatase assay. Immobilization through passive chemisorption proved to be efficient in capturing the complementary target DNA with a detection limit of 0.14 nM and sensitivity of 9.38 A M-1 cm2. In general, this work presents a comprehensive understanding of cleaning, modification and performance of gold-sputtered microelectrodes with built-in gold reference and counter electrodes for both fundamental investigations and practical DNA sensing applications.


C-reactive protein and coronary heart disease: a critical review.
Modestly elevated baseline concentrations of C-reactive protein (CRP), the classical acute phase protein, are associated with the long-term risk of coronary heart disease in general populations, whilst the major acute phase response of CRP following myocardial infarction is associated with death and cardiac complications. The pathogenic and clinical significance of these associations is controversial. Here we critically review the evidence and describe large-scale epidemiological studies, novel experiments and possible specific therapies which will rigorously inform the debate. We distinguish between the potential pathogenicity of high acute phase circulating CRP concentrations in individuals with substantial tissue damage and modest but persistent increases in baseline values in generally healthy subjects.


Crosstalk of necroptosis and pyroptosis defines tumor microenvironment characterization and predicts prognosis in clear cell renal carcinoma.
Pyroptosis and necroptosis are two recently identified forms of immunogenic cell death in the tumor microenvironment (TME), indicating a crucial involvement in tumor metastasis. However, the characteristics of necroptosis and pyroptosis that define tumor microenvironment and prognosis in ccRCC patients remain unknown. We systematically investigated the transcriptional variation and expression patterns of Necroptosis and Pyroptosis related genes (NPRGs). After screening the necroptosis-pyroptosis clusters, the potential functional annotation for clusters was explored by GSVA enrichment analysis. The Necroptosis-Pyroptosis Genes (NPG) scores were used for the prognosis model construction and validation. Then, the correlations of NPG score with clinical features, cancer stem cell (CSC) index, tumor mutation burden (TMB), TME, and Immune Checkpoint Genes (ICGs) were also individually explored to evaluate the prognosis predictive values in ccRCC. Microarray screenings identified 27 upregulated and 1 downregulated NPRGs. Ten overall survival associated NPRGs were filtered to construct the NPG prognostic model indicating a better prognostic signature for ccRCC patients with lower NPG scores (P< 0.001), which was verified using the external cohort. Univariate and multivariate analyses along with Kaplan-Meier survival analysis demonstrated that NPG score prognostic model could be applied as an independent prognostic factor, and AUC values of nomogram from 1- to 5- year overall survival with good agreement in calibration plots suggested that the proposed prognostic signature possessed good predictive capabilities in ccRCC. A high-/sNPG score is proven to be connected with tumor growth and immune-related biological processes, according to enriched GO, KEGG, and GSEA analyses. Comparing patients with a high-NPG score to those with a low-NPG score revealed significant differences in clinical characteristics, growth and recurrence of malignancies (CSC index), TME cell infiltration, and immunotherapeutic response (P< 0.005), potentially making the NPG score multifunctional in the clinical therapeutic setting. Furthermore, AIM2, CASP4, GSDMB, NOD2, and RBCK1 were also found to be highly expressed in ccRCC cell lines and tumor tissues, and GASP4 and GSDMB promote ccRCC cells' proliferation, migration, and invasion. This study firstly suggests that targeting the NPG score feature for TME characterization may lend novel insights into its clinical applications in the prognostic prediction of ccRCC.


Incidence rate of stroke in Peru.
To determine the incidence of stroke, overall and by sub-types, in Peru between 2017 and 2018. Analysis of hospital morbidity data obtained from SUSALUD (open data). Using the ICD-10 codes, the following were studied: subarachnoid hemorrhage (I60), atraumatic intracerebral hemorrhage (I61), cerebral infarction (I63), and unspecified stroke (I64). The crude and age-standardized incidence was calculated according to the population of the World Health Organization and using the national projected population number of people according to year, age and sex as the denominator. In 2017, a total of 10,570 stroke cases were recorded, whereas, in 2018, there were 12,835 cases. Ischemic events were more frequent in both years. Regardless of stroke subtype and year, men were more affected than women. In the 35+ year-old population, an increase in the crude incidence of total stroke was observed between 2017 and 2018, from 80.9 to 96.7 per 100,000 person-years. The age-standardized incidence showed the same trend, but in a greater magnitude: from 93.9 to 109.8 per 100,000 person-years. Ischemic stroke was the one that increased the most, with an age-standardized rate in people aged 35+ years of 35.2 in 2017 and 46.3 per 100,000 person-years in 2018. The incidence of stroke is high in Peru. Ischemic cases are the most frequent and they disproportionately affect men. Our results suggest the need for a surveillance system to robustly quantify the incidence of these cases and understand their determinants.


Endothelin-mediated effect of erythropoietin on blood pressure and renal hemodynamics in hypertensive rats.
Erythropoietin (EPO) has been reported to induce hypertension in hemodialysis patients with family history of hypertension. In this study, to reveal the mechanism of EPO-induced hypertension, we examined the acute effect of EPO on blood pressure (BP) and renal hemodynamics in genetically hypertensive rats, and we also tested the effect of BQ-123, an endothelin ETA-receptor blocker, on EPO-induced changes in hemodynamics. Male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY), aged 9-12 wk, were anesthetized, and BP was monitored through the carotid artery. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured before and after an intravenous injection of EPO (1,000 U/kg body wt). In another group of SHR, BQ-123 was continuously infused (1.2 mg.kg body wt-1.h-1) during the experiments. The acute injections of EPO increased BP significantly in SHR in a dose-dependent manner, whereas WKY did not show a significant increase in BP after EPO injections. The effect of EPO on BP in SHR was blocked by BQ-123. In SHR, an acute injection of EPO decreased RPF significantly (from 1.78 +/- 0.16 to 1.49 +/- 0.18 ml.min-1.100 g body wt-1, P < 0.05) without a change in GFR, whereas WKY did not show significant changes in either RPF or GFR. The effect of EPO on RPF in SHR was completely blocked by BQ-123 (from 1.92 +/- 0.26 to 1.88 +/- 0.28 ml.min-1.100 g wt-1, NS). EPO caused a significant increase in plasma endothelin ET-1 in SHR (from 2.3 +/- 0.6 to 6.3 +/- 1.6 pg/ml, P < 0.05), but not in WKY. In conclusion, acute administration of EPO raised blood pressure and reduced RPF in SHR, and these vasoconstrictive effects of EPO are mediated via ETA receptors by an enhanced ET-1 release.


Accuracy of PfHRP2 versus Pf-pLDH antigen detection by malaria rapid diagnostic tests in hospitalized children in a seasonal hyperendemic malaria transmission area in Burkina Faso.
In most sub-Saharan African countries malaria rapid diagnostic tests (RDTs) are now used for the diagnosis of malaria. Most RDTs used detect Plasmodium falciparum histidine-rich protein-2 (PfHRP2), though P. falciparum-specific parasite lactate dehydrogenase (Pf-pLDH)-detecting RDTs may have advantages over PfHRP2-detecting RDTs. Only few data are available on the use of RDTs in severe illness and the present study compared Pf-pLDH to PfHRP2-detection. Hospitalized children aged one month to 14 years presenting with fever or severe illness were included over one year. Venous blood samples were drawn for malaria diagnosis (microscopy and RDT), culture and complete blood count. Leftovers were stored at -80 °C and used for additional RDT analysis and PCR. An RDT targeting both PfHRP2 and Pf-pLDH was performed on all samples for direct comparison of diagnostic accuracy with microscopy as reference method. PCR was performed to explore false-positive RDT results. In 376 of 694 (54.2%) included children, malaria was microscopically confirmed. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value were 100.0, 70.9, 69.4 and 100.0%, respectively for PfHRP2-detection and 98.7, 94.0, 91.6 and 99.1%, respectively for Pf-pLDH-detection. Specificity and PPV were significantly lower for PfHRP2-detection (p <0.001). For both detection antigens, specificity was lowest for children one to five years and in the rainy season. PPV for both antigens was highest in the rainy season, because of higher malaria prevalence. False positive PfHRP2 results were associated with prior anti-malarial treatment and positive PCR results (98/114 (86.0%) samples tested). Among children presenting with severe febrile illness in a seasonal hyperendemic malaria transmission area, the present study observed similar sensitivity but lower specificity and PPV of PfHRP2 compared to Pf-pLDH-detection. Further studies should assess the diagnostic accuracy and safety of an appropriate Pf-pLDH-detecting RDT in field settings and if satisfying, replacement of PfHRP2 by Pf-pLDH-detecting RDTs should be considered.


Cytotoxicity of isoproterenol to cultured heart cells: effects of antioxidants on modifying membrane damage.
Primary cultures of rat myocytes were used to study the cardiac damage induced by toxic doses of L-isoproterenol (ISO). Cultures were exposed to varying concentrations of ISO (2.4 X 10(-5), 1 X 10(-4), and 5 X 10(-4) M) for 0.5, 1.5, 4, and 12 hr. Mitochondrial membrane fragility, myocyte potassium content (as an index of sarcolemmal damage), and cellular glutathione content were used to evaluate cellular injury. A significant increase in mitochondrial fragility was observed 0.5 hr after treatment with 5 X 10(-4) M ISO. Lower doses caused an increase in mitochondrial fragility 1.5 hr after exposure. Longer durations of ISO exposure (4 and 12 hr) were necessary to decrease cellular potassium content. Glutathione levels were minimally affected by ISO. L-Ascorbic acid (5 X 10(-3) M) or sodium bisulfite (9.6 X 10(-4) M) were added to the cultures to determine if antioxidants prevent the toxicity caused by ISO. The presence of L-ascorbic acid or sodium bisulfite in ISO-treated myocyte cultures prevented the toxic changes in mitochondrial fragility and myocyte potassium content. The data indicate that antioxidants may be useful in reducing injury induced by toxic doses of ISO. Furthermore, mitochondrial injury may be involved significantly with the development of ISO-induced cardiotoxicity.


Towards multiscale plant models: integrating cellular networks.
One of the ambitions of 'crop systems biology' is to combine information from molecular biology with a broader view of plant development and growth. In the context of modeling, this calls for a multiscale perspective that focuses on the interplay between cellular and macroscopic studies. With this in mind, in this review we aim to draw attention to a panel of approaches that were developed in the context of systems biology and are used for analyzing and describing the behavior of cellular networks. Ultimately, insights obtained from these methods can be exploited to refine the description of plant processes, leading to integrated plant-cellular models.


Multigenerational transmission of liability to psychiatric illness in offspring of parents with bipolar disorder.
Instead of the typical assessment of risk of illness in the offspring based on a parent with bipolar disorder, we explored the potential multigenerational conveyance across several disorders of the vulnerability to illness in the offspring of a patient with bipolar disorder. A total of 968 outpatients (average age 41 years) with bipolar illness gave informed consent and filled out a detailed questionnaire about a family history in their parents, grandparents, and offspring of: depression; bipolar disorder; alcohol abuse; substance abuse; suicide attempt; or "other" illness. Of those with children, 346 were from the USA and 132 were from Europe. Amount and type of illness in progenitors in two and three previous generations were related to offspring illness. The type of illness seen in both prior generations was associated with the same type of illness in the offspring of a bipolar patient, including depression, bipolar disorder, alcohol and substance abuse and "other" illness, but not suicide attempts. There was an impact of multiple generations, such that depression in grandparents and/or great-grandparents increased the risk of depression in the offspring from 12.6% to 41.4%. A family history of illness burden in prior generations was previously related to an earlier age of onset of bipolar illness in our adult patients with bipolar disorder and is now also found to be related to the incidence of multiple psychiatric illnesses in their offspring. Genetic and epigenetic mechanisms deserve consideration for this multigenerational conveyance of illness vulnerability, and clinical and public health attempts to prevent or slow this transmission are indicated.


Structure and mechanism of a bacterial light-regulated cyclic nucleotide phosphodiesterase.
The ability to respond to light is crucial for most organisms. BLUF is a recently identified photoreceptor protein domain that senses blue light using a FAD chromophore. BLUF domains are present in various proteins from the Bacteria, Euglenozoa and Fungi. Although structures of single-domain BLUF proteins have been determined, none are available for a BLUF protein containing a functional output domain; the mechanism of light activation in this new class of photoreceptors has thus remained poorly understood. Here we report the biochemical, structural and mechanistic characterization of a full-length, active photoreceptor, BlrP1 (also known as KPN_01598), from Klebsiella pneumoniae. BlrP1 consists of a BLUF sensor domain and a phosphodiesterase EAL output domain which hydrolyses cyclic dimeric GMP (c-di-GMP). This ubiquitous second messenger controls motility, biofilm formation, virulence and antibiotic resistance in the Bacteria. Crystal structures of BlrP1 complexed with its substrate and metal ions involved in catalysis or in enzyme inhibition provide a detailed understanding of the mechanism of the EAL-domain c-di-GMP phosphodiesterases. These structures also sketch out a path of light activation of the phosphodiesterase output activity. Photon absorption by the BLUF domain of one subunit of the antiparallel BlrP1 homodimer activates the EAL domain of the second subunit through allosteric communication transmitted through conserved domain-domain interfaces.


The Relationship Between Hemoglobin Glycation Variation Index and Vitamin D in Type 2 Diabetes Mellitus.
This study aimed to investigate the relationship between hemoglobin glycation variation index (HGI) and vitamin D in patients with type 2 diabetes mellitus (T2DM). This is a cross-sectional study that recruited 347 patients with T2DM. The subjects were divided into no vitamin D deficiency group (25(OH)D ≥20 ng/mL) and vitamin D deficiency group (25(OH)D < 20 ng/mL). HGI was calculated as the difference between the measured and predicted values of HbA1c using the linear relationship between HbA1c level and fasting plasma glucose levels. All study participants were divided into high HGI and low HGI groups using the median of HGI as the boundary. At last, the subjects were divided into male group and female group, and these groups were further subdivided into vitamin D deficiency group and no vitamin D deficiency group. The levels of HGI were significantly higher in the vitamin D deficiency group compared with the no vitamin D deficiency group for all patients. The same was true for female patients but not for male patients. The prevalence of vitamin D deficiency in the high HGI group was higher than that in the low HGI group. The high HGI group had lower vitamin D levels compared to the low HGI group. Compared to the male group, the female group had lower vitamin D levels but higher HGI levels. A negative correlation existed between 25(OH) D and HGI in all subjects, as well as in the female-only subgroups. In the male-only subgroups, there was no correlation between them, and this positive correlation still existed after adjusting for other factors in multilinear regression analysis. Our study showed for the first time that HGI is inversely associated with vitamin D in all patients with T2DM, and the correlation was also found in female patients, but not in male patients.


Phosphatidylserine-containing liposomes inhibit the differentiation of osteoclasts and trabecular bone loss.
Liposomes containing phosphatidylserine (PS) are engulfed by phagocytes including macrophages, microglia, and dendritic cells. PS liposomes (PSLs) mimic the effects of apoptotic cells on these phagocytes to induce the secretion of anti-inflammatory molecules and to inhibit the maturation of dendritic cells. However, the effects of PSLs on osteoclasts, which are also differentiated from the common myeloid precursors, remain to be determined. This study investigated the effects of PSLs on the osteoclastogenesis. In the rat bone marrow culture system, osteoclast precursors phagocytosed PSLs to secrete TGF-beta1 and PGE(2), which in turn inhibited osteoclastogenesis through the downregulation of receptor activator for NF-kappaB ligand, receptor activator of NF-kappaB, ICAM-1, and CD44. Consistent with these in vitro observations, i.m. injection of PSLs significantly increased the plasma level of TGF-beta1 and PGE(2) and decreased the expression of receptor activator for NF-kappaB ligand, receptor activator of NF-kappaB, and ICAM-1 in the skeletal tissues of ankle joints of rats with adjuvant arthritis (AA). A quantitative analysis using microcomputed tomography revealed that PSLs as well as TGF-beta1 together with PGE(2) significantly inhibited AA-induced trabecular bone loss. These observations strongly suggest that PSLs generate TGF-beta1 and PGE(2) release, leading to inhibit osteoclastogenesis and AA-induced trabecular bone loss. Because PS is a component of the cell membrane, PSLs therefore can be a potentially effective pharmacological intervention against abnormal bone loss, such as osteoporosis without deleterious side effects.


Doxorubicin combined with betulinic acid or lonidamine in RGD ligand-targeted pH-sensitive micellar system for ovarian cancer treatment.
Synergistic combination therapy involving the integration of chemotherapeutics and chemosensitizers into micelles has demonstrated great potential for tumor-specific location release. Here, the natural product betulinic acid (BA) and chemical drug lonidamine (LN) were used as chemosensitizers in combination with doxorubicin (DOX) for ovarian cancer treatment. We designed pH-sensitive peptide derivatives and constructed an all-in-one multifunctional multidrug pH-sensitive targeting delivery system for the synergistic co-delivery of DOX and BA (or LN). The combination of DOX and BA was found to elicit better therapeutic effects and lower cardiotoxicity than the DOX and LN combination in Skvo3 cells. Further, loading DOX/BA into the present micellar systems enabled burst release at the tumor location, leading to enhanced anti-tumor effects and reduced off-target effects. More importantly, DOX/BA micelles elicited fewer adverse effects on cardiac function and leukocyte counts in Skvo3 subcutaneous xenograft models. These features suggest that the designed micelles represent a promising multifunctional strategy for the efficient treatment of ovarian cancer.


Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial.
Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutaneously every other day for at least 2 y. Some remained randomised for up to 5 y but, subsequently, patients received treatment according to physicians' discretion. Patients were re-contacted and asked to participate. Efficacy related measures included MRI parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS. Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% (20/109) for placebo versus 8.3% (9/108) for IFNB-1b 50 microg and 5.4% (6/111) for IFNB-1b 250 microg). The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 microg or 250 microg. The dataset provides important resources to explore early predictors of long-term outcome.


Accurate characterization of complex Bloch modes in optical chain waveguides using real-valued computations.
This research presents a highly accurate and easy-to-implement method to characterize the complex Bloch modes propagating along optical chain waveguides with three-dimensional (3D) layered geometries and dispersive negative-epsilon material compositions. The technique combines commercial EM solver results with analytical post-processing to avoid iterative complex root estimation on the complex plane. The proposed methodology is based on the real-valued computations that yield the complex Bloch wavevector with superior accuracy even when both radiation and material losses are present. In addition, we introduce a single unit-cell technique to provide the possibility of dense meshing of 3D geometries when available computational resources are limited. To verify our results, two different plasmonic and dielectric case studies are discussed. The obtained results agree well with numerical and experimental results from the literature. Due to its generality, robustness, and high accuracy, the method is beneficial for studying a large variety of waveguide-based nanophotonic components.


Risk factors for early death in patients bridged to transplant with continuous-flow left ventricular assist devices.
Recent evidence suggests patients bridged to heart transplant (BTT) have equivalent outcomes as those undergoing conventional orthotopic heart transplantation (OHT). However, data on risk factors for early death in BTT patients are limited. We retrospectively reviewed the United Network for Organ Sharing database of all patients bridged to OHT with a HeartMate II from January 2005 to December 2010. The primary outcome was all-cause 90-day mortality. Additional postoperative outcomes were cerebrovascular accident and need for renal replacement therapy. Kaplan-Meier analysis assessed survival. Preoperative variables associated with 90-day death on univariate analysis (p<0.2) were included in a multivariable Cox proportional hazards regression. A HeartMate II was used to bridge 1,312 patients (average age, 52±12 years) to OHT, most commonly for idiopathic cardiomyopathy (50.7%). During the study, 171 patients (13.0%) died. The unadjusted 90-day survival was 92.3%. The highest annual average center volume in this cohort, examining for BTT recipients only, was 28 BTT procedures yearly. Postoperative cerebrovascular accident occurred in 29 patients (2.2%), and 106 (8.3%) required renal replacement therapy. Cox regression revealed age, glomerular filtration rate, African American race, human leukocyte antigen mismatch, serum bilirubin, need for mechanical ventilation, donor age, and prolonged ischemia time were associated with 90-day death. Early survival was improved for patients who underwent OHT at high-volume centers (p=0.01). This study examining risk factors for early death in patients bridged to OHT using HeartMate II mechanical assistance will aid in identifying patients best suited to benefit from this technology.


Nutrition and prostate cancer: a review.
Despite intense efforts, little is known about the etiology of prostate cancer, and treatment of advanced forms of the disease has had limited success. Nonetheless, epidemiologic studies combined with animal model and in vitro experiments indicate that natural components of the diet, including n-3 PUFA, the carotenoid lycopene, and the trace element selenium, may serve as chemopreventive agents that suppress the growth and dissemination of neoplastic prostate cells. Until further study, however, soy isoflavones should be viewed with some caution, especially as adjuvant's to chemotherapy, in patients with hormone-refractory prostate cancer. Future studies, using different forms and doses of selenium and tomato carotenoids, may shed new light on the etiology and prevention of prostate cancer.


Antimicrobial stewardship in transplant patients.
To provide an update on the current landscape of antimicrobial stewardship in solid organ transplant (SOT) recipients. Constructing personalized antimicrobial prescribing approaches to avoid untoward consequences of antimicrobials while improving outcomes is an emerging and critical aspect of transplant medicine. Stewardship activities encompassing the specialized interests of transplant patients and programs are evolving. New literature evaluating strategies to optimize antimicrobial agent selection, dosing, and duration have been published. Additionally, consensus guidance for certain infectious clinical syndromes is available and should inform institutional clinical practice guidelines. Novel metrics for stewardship-related outcomes in transplantation are desperately needed. Though exciting new molecular diagnostic technologies will likely be pivotal in the care of immunocompromised patients, optimal clinical adaptation and appropriate integration remains unclear. Important studies understanding the behaviors influencing antimicrobial prescribing in organizational transplant cultures are needed to optimize interventions. Consequences of antimicrobial use, such as Clostridiodes difficile and infections with multidrug-resistant organisms disproportionately affect SOT recipients and are associated with poor allograft and patient outcomes. Application of ASP interventions tailored to SOT recipients is recommended though further studies are needed to provide guidance for best practice.


Re-evaluation of the "law of constant extinction" for ruminants at different taxonomical scales.
The "law of constant extinction," proposed by Van Valen, states that long and short-lived taxa have equal chances of going extinct. This pattern of age-independent extinction was originally inferred using the fossil record of several different taxa and relied on survivorship curves built from the literal reading of the fossil record. Van Valen's seminal work was mostly done at higher taxonomic levels, hence its prevalence at the species level could not be directly inferred. The surprisingly few subsequent studies done at the species level have challenged the prevalence of age-independent extinction, but those have, for the most part, failed to explicitly incorporate inherent biases of the fossil record. Using a recent Bayesian framework that accounts for several of those biases, including the fact that very short-living lineages might never make to the record itself, we showed that Ruminantia species present age-dependent extinction, where extinction probability decreases with species age. An analysis at the genus level suggested age-independent extinction but further examination suggested that the pattern might be more complex than previously reported by Van Valen. Our results indicate that different taxonomic levels may present different extinction regimes, which could justify the development of new macroevolutionary theory and methods.


Immunoregulation of Neutrophil Extracellular Trap Formation by Endothelial-Derived p33 (gC1q Receptor).
The formation of neutrophil extracellular traps (NETs) is a host defence mechanism, known to facilitate the entrapment and growth inhibition of many bacterial pathogens. It has been implicated that the translocation of myeloperoxidase (MPO) from neutrophilic granules to the nucleus is crucial to this process. Under disease conditions, however, excessive NET formation can trigger self-destructive complications by releasing pathologic levels of danger-associated molecular pattern molecules (DAMPs). To counteract such devastating immune reactions, the host has to rely on precautions that help circumvent these deleterious effects. Though the induction of DAMP responses has been intensively studied, the mechanisms that are used by the host to down-regulate them are still not understood. In this study, we show that p33 is an endothelial-derived protein that has the ability to annul NET formation. We found that the expression of human p33 is up-regulated in endothelial cells upon infections with Streptococcus pyogenes bacteria. Using tissue biopsies from a patient with streptococcal necrotising fasciitis, we monitored co-localisation of p33 with MPO. Further in vitro studies revealed that p33 is able to block the formation of DAMP-induced NET formation by inhibiting the enzymatic activity of MPO. Additionally, mice challenged with S. pyogenes bacteria demonstrated diminished MPO activity when treated with p33. Together, our results demonstrate that host-derived p33 has an important immunomodulating function that helps to counterbalance an overwhelming DAMP response.


Flexible endoscopy simulators.
Training in flexible endoscopy is becoming increasingly complex. In an effort to improve the efficiency of endoscopic education, physicians are turning to simulation technology to provide a platform for training away from the endoscopy suite. The concept of medical simulation is not new, but the recent addition of powerful computer-generated virtual reality simulation has revolutionized the field. These compact computers are now able to generate a simulated environment that not only mimics the movement of the endoscope, but also recreates the sounds of the endoscopy suite, the feel of the movement of the scope, the reaction of intestinal tissue, and the response of a patient experiencing discomfort. Within this life-like simulated environment, a wide variety of diagnostic and therapeutic endoscopic procedures can be performed. This article reviews the history of flexible endoscopy simulators and details the most advanced models currently available. The literature supporting the use of these simulators is also presented, and issues involving the incorporation of simulation technology into endoscopic education and credentialing are discussed.


[Role of synovial plicae in pathology of the knee].
Medial synovial plicae are a cause of internal derangement of the knee in less than 3 p. 100 of cases. The diagnosis of a symptomatic plica is made on clinical and arthroscopic findings. Superior plicae are generally not pathological. When associated with another cause of internal derangement, a medial plica is generally not pathological.


Multistage genome-wide association meta-analyses identified two new loci for bone mineral density.
Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.


Statewide Longitudinal Progression of the Whole-Patient Measure of Safety in South Carolina.
Meaningful improvement in patient safety encompasses a vast number of quality metrics, but a single measure to represent the overall level of safety is challenging to produce. Recently, Perla et al. established the Whole-Person Measure of Safety (WPMoS) to reflect the concept of global risk assessment at the patient level. We evaluated the WPMoS across an entire state to understand the impact of urban/rural setting, academic status, and hospital size on patient safety outcomes. The population included all South Carolina (SC) inpatient discharges from January 1, 2008, through to December 31, 2013, and was evaluated using established definitions of highly undesirable events (HUEs). Over the study period, the proportion of hospital discharges with at least one HUE significantly decreased from 9.7% to 8.8%, including significant reductions in nine of the 14 HUEs. Academic, large, and urban hospitals had a significantly lower proportion of hospital discharges with at least one HUE in 2008, but only urban hospitals remained significantly lower by 2013. Results indicate that there has been a decrease in harm events captured through administrative coded data over this 6-year period. A composite measure, such as the WPMoS, is necessary for hospitals to evaluate their progress toward reducing preventable harm.


Organization and alternative splicing of the Caenorhabditis elegans cAMP-dependent protein kinase catalytic-subunit gene (kin-1).
The cAMP-dependent protein kinase (protein kinase A, PK-A) is multifunctional in nature, with key roles in the control of diverse aspects of eukaryotic cellular activity. In the case of the free-living nematode, Caenorhabditis elegans, a gene encoding the PK-A catalytic subunit has been identified and two isoforms of this subunit, arising from a C-terminal alternative-splicing event, have been characterized [Gross, Bagchi, Lu and Rubin (1990) J. Biol. Chem. 265, 6896-6907]. Here we report the occurrence of N-terminal alternative-splicing events that, in addition to generating a multiplicity of non-myristoylatable isoforms, also generate the myristoylated variant(s) of the catalytic subunit that we have recently characterized [Aspbury, Fisher, Rees and Clegg (1997) Biochem. Biophys. Res. Commun. 238, 523-527]. The gene spans more than 36 kb and is divided into a total of 13 exons. Each of the mature transcripts contains only 7 exons. In addition to the already characterized exon 1, the 5'-untranslated region and first intron actually contain 5 other exons, any one of which may be alternatively spliced on to exon 2 at the 5' end of the pre-mRNA. This N-terminal alternative splicing occurs in combination with either of the already characterized C-terminal alternative exons. Thus, C. elegans expresses at least 12 different isoforms of the catalytic subunit of PK-A. The significance of this unprecedented structural diversity in the family of PK-A catalytic subunits is discussed.


[Current use and possible future applications of the magnetization transfer technique in neuroradiology].
Magnetization transfer (MT) imaging is a special MR technique used for selective suppression of the MR signal of protons bound on macromolecules. The most important applications in neuroradiology are (1) detection of subtle changes in otherwise normal-appearing cerebral white matter, for instance in multiple sclerosis (MS), Wallerian degeneration, and hydrocephalus, (2) differentiation of white matter lesions with high signal on T (2)-weighted MR-images, like MS plaques, brain infarctions, and brain edema, (3) follow-up of cerebral white matter diseases using volumetric MT techniques, and (4) improvement in delineating of contrast enhancing brain lesions, such as cerebral metastases. We describe the physical rationale of the MT technique and present the most important current and possible future applications of MT imaging to answer clinical and scientific questions in neuroradiology.


The early origins of chronic heart failure: impaired placental growth and initiation of insulin resistance in childhood.
Low birth weight and low placental weight predict later coronary heart disease and hypertension. This has led to the hypothesis that these diseases are initiated by foetal programming, the process by which foetal malnutrition leads to permanent changes in the body in ways that lead to chronic disease in later life. Here we examine the association between body and placental size at birth and later chronic heart failure. We identified 187 patients taking medications for chronic heart failure in a birth cohort of 13,345 people born in Helsinki, Finland during 1934-44. Chronic heart failure was associated with a small placental surface area. In people born with a placental area less than 225 cm(2), the odds ratio for chronic heart failure was 1.7 (1.1-2.5), compared with people born with a placental area greater than 295 cm(2). The risk of heart failure was further increased by rapid gain in body mass index after the age of 2 years, a path of growth known to be linked to insulin resistance in later life. In a simultaneous regression, low body mass index at 2 years and high body mass index at 11 years were each associated with chronic heart failure (P = 0.008 and 0.001, respectively). Chronic heart failure in adult life may be initiated by impaired placental growth which adversely affects cardiac development. People born with a vulnerable heart are more likely to develop chronic heart failure if they become insulin resistant.


Influence of socioeconomic status on the effectiveness of bicycle helmet legislation for children: a prospective observational study.
To evaluate the influence of average family income in a geographic area on the effectiveness of helmet legislation on observed helmet use by children (5-14 years). The study was conducted in East York, a health district of Metropolitan Toronto, in collaboration with the East York Health Unit. In 1996, the total population was 107 822, 11 340 of which were children 5 to 14 years. Census data were used to group the 21 census tracts in East York into 7 geographically distinct areas. The boundaries of these areas are natural barriers to travel, such as expressways, ravines, railway tracks, and hydroelectric power lines. The areas were also ranked according to average family income (based on Statistics Canada data). For analytical purposes, areas were defined as low-, mid-, and high-income areas. Census data profiles of the areas have been previously described. For each consecutive year from 1990 to 1997 inclusive, direct observations of children riding bicycles in East York during the months of April through October were made. In 1995, observations were completed before the introduction of the law on October 1, 1995. Only children who were between 5 and 14 years of age and riding a 2-wheeled bicycle were included in the study. In total, 111 sites across all 7 areas were selected for observation. Observational sites included school yards of all elementary and middle schools (kindergarten to grade 8) and all parks in East York. In addition, 5 major intersections and 5 residential streets from each area were randomly selected. Observers were trained and used a standardized data collection form. A pilot study showed that the data collected by observers were reliable and valid. Observers remained at each site for 1 hour and collected data on helmet use and sex. Ethical approval for the study was obtained from the Hospital for Sick Children Research Ethics Board, the East York Board of Education, and the Metropolitan Separate School Board. The proportion of children who were wearing a bicycle helmet was estimated by year (1990-1997, inclusive), sex (male, female), location (school, park, major intersection, residential street), and income area (low, mid, high). For estimating the effect of legislation on helmet use, data from the year immediately after legislation (1996) were compared with data from the year preceding legislation (1995). The relative risk (RR) of helmet use (after vs before legislation) was calculated along with a 95% confidence interval (CI). Logistic regression analysis was used to adjust for potential confounding variables (sex and location). During the 8-year study period, 9768 observations were made (range: 914-1879 observations per year). The proportion of child cyclists who wore a bicycle helmet increased steadily during the first 4 years of the study period, from 4% in 1990 (34 of 914), to 16% in 1991 (303 of 1879), to 25% in 1992 (383 of 1563), and to 45% in 1993 (438 of 984). During 1994 (460 of 1083) and 1995 (568 of 1227), helmet use remained relatively stable at approximately 44%. Helmet use rose markedly in 1996 (the first year after helmet legislation was introduced) to 68% (818 of 1202) and remained stable at 66% (609 of 916) in 1997. Throughout the study period, girls were consistently more likely to wear helmets than were boys. In total, 47% (1420 of 3047) of girls wore helmets, compared with 33% (2193 of 6721) of boys (RR: 1.43; 95% CI: 1.36-1.50). In addition, children who were riding to school were more likely to use helmets, compared with children who were riding on residential streets, major intersections, and parks. Overall, 48% (1497 of 3129) of children who were riding to school wore bicycle helmets, compared with 32% (2116 of 6639) of children who were riding at other locations (RR: 1.50; 95% CI: 1.43-1.58). Children in the high-income areas were consistently more likely to wear helmets, compared with children in the mid- and low-income areas. Helmet legislation was associated with a significant increase in helmet use by children in East York. In 1995, 46% (ast York. In 1995, 46% (568 of 1227) of children wore bicycle helmets, compared with 68% (818 of 1202) of children in 1996 (RR: 1.47; 95% CI: 1.37-1.58). The effect of legislation, however, varied by income area. In low-income areas, helmet use increased by 28% after legislation, from 33% (213 of 646) in 1995 to 61% (442 of 721) in 1996 (RR: 1.86; 95% CI: 1.64-2.11). In mid-income areas, helmet use increased by 29% after legislation, from 50% (150 of 300) in 1995 to 79% (185 of 234) in 1996 (RR: 1.58; 95% CI: 1.39-1.80). In high-income areas, helmet use increased by only 4%, from 73% (205 of 281) in 1995 to 77% (191 of 247) in 1996 (RR: 1.06; 95% CI: 0.96-1.17). This finding of a significant increase in helmet use after legislation in low- and mid-income areas but not in high-income areas remained even after logistic regression analysis adjusted for sex and location. This study showed that bicycle helmet use by children increased significantly after helmet legislation. In this urban area with socioeconomic diversity and in the context of prelegislation promotion and educational activities, the legislative effect was most powerful among children who resided in low-income areas.


[Analysis of prescriptions for mass-produced drugs from various pharmacotherapeutic groups. Diuretics].
The present paper links up with the studies carried out at the Department of Organization and Management of Pharmacy within the framework of a grant. It analyzes prescription of diuretics, the characteristics of identification being age and sex. Also the frequency of occurrence of diseases and the individual diagnoses according to the International Statistical Classification, 10th revision, were examined. The authors analyzed the assortment structure of the diuretics prescribed (number of medical prescriptions, number of packages) and examined which mass-produced preparations from other pharmacotherapeutic groups were prescribed in combination with diuretics. The analysis was made in a pharmacy of the Region of East Slovakia-City in the year 1995. The source of information were the medical prescriptions issued in the selected pharmacy.


Flavonoid intake from vegetables and fruits is inversely associated with colorectal cancer risk: a case-control study in China.
Flavonoids may play an important role in the protective effects of vegetables, fruits and tea against colorectal cancer. However, associations between flavonoids and colorectal cancer risk are inconsistent, and a few studies have evaluated the effect of flavonoids from different dietary sources separately. This study aimed to evaluate associations of flavonoids intake from different dietary sources with colorectal cancer risk in a Chinese population. From July 2010 to December 2015, 1632 eligible colorectal cancer cases and 1632 frequency-matched controls (age and sex) completed in-person interviews. A validated FFQ was used to estimate dietary flavonoids intake. Multivariate logistical regression models were used to calculate the OR and 95 % CI of colorectal cancer risk after adjusting for various confounders. No significant association was found between total flavonoids and colorectal cancer risk, with an adjusted OR of 1·06 (95 % CI 0·85, 1·32) comparing the highest with the lowest quartile. Anthocyanidins, flavanones and flavones intakes from total diet were found to be inversely associated with colorectal cancer risk. Compared with the lowest quartile, the adjusted OR for the highest quartile were 0·80 (95 % CI 0·64, 1·00) for anthocyanidins, 0·28 (95 % CI 0·22, 0·36) for flavanones and 0·54 (95 % CI 0·43, 0·67) for flavones. All subclasses of flavonoids from vegetables and fruits were inversely associated with colorectal cancer. However, no significant association was found between tea flavonoids and colorectal cancer risk. These data indicate that specific flavonoids, specifically flavonoids from vegetables and fruits, may be linked with the reduced risk of colorectal cancer.


Charnley total hip arthroplasty with cement. Minimum twenty-five-year follow-up.
This report presents the results of the senior author's initial twenty-five-year experience with the use of Charnley total hip arthroplasty with cement. The purpose of this paper was to evaluate the long-term results of total hip arthroplasty. Between July 1970 and April 1972, the senior author (R. C. J.) performed 330 Charnley total hip replacements with cement using a hand-packing cement technique in 262 patients. Fifty-one patients (sixty-two hips) who were alive at least twenty-five years post-operatively were evaluated from a clinical standpoint with use of a standard-terminology questionnaire. The average age of this group at the time of surgery was fifty-six years (range, thirty-five to seventy-one years) compared with sixty-five years (range, twenty-one to eighty-nine years) for the entire group. All patients were evaluated for radiographic changes at the time of their most recent follow-up. Of the fifty-one patients (sixty-two hips) who were alive at least twenty-five years postoperatively, thirty-one (thirty-six hips) had a follow-up radiograph made at a minimum of twenty-five years after the surgery. The average duration of radiographic follow-up for the fifty-one patients was 22.7 years (range, two to twenty-seven years). Of the sixty-two hips in the fifty-one patients who were alive at least twenty-five years postoperatively, fourteen (23 percent) had been revised. Three (5 percent) had the revision because of loosening with infection; eleven (18 percent), because of aseptic loosening; and none, because of dislocation. The prevalence of revision due to aseptic loosening of the acetabular component in all 316 hips (excluding those that were lost to follow-up or that were revised for infection or dislocation) was 6 percent (eighteen hips), whereas the prevalence in the fifty-nine hips (excluding the three revised for infection) in the patients who were alive at least twenty-five years after the arthroplasty was 15 percent (nine hips). The prevalence of revision because of aseptic loosening of the femoral component in all 316 hips was 3 percent (nine hips), and the prevalence in the fifty-nine hips in the living patients was 7 percent (four hips). In the group of living patients, osteolysis occurred in Gruen zone 1 or 7 in thirty-three hips and in Gruen zones 2 through 6 in two hips. Ballooning acetabular osteolysis occurred in five hips. Of the 327 hips for which the outcome was known after a minimum of twenty-five years, 295 (90 percent) had retained the original implants until the patient died or until the most recent follow-up examination. Of the sixty-two hips in patients who lived for at least twenty-five years after the surgery, forty-eight (77 percent) had retained the original prosthesis. Our follow-up study at twenty-five years following Charnley total hip arthroplasty with cement demonstrates the durability of the results of the procedure. These results should provide a means for comparison with the results of newer cementing techniques as well as those associated with newer cemented and cementless hip designs.


Ultrastructural comparison between regenerating and developing hindlimbs of Xenopus laevis tadpoles.
Hindlimbs of Xenopus laevis tadpoles at stages 50 to 55 of embryonic development were amputated in order to study the fine structure associated with ontogenetic decline in regenerative ability of this anuran. Regenerating hindlimbs were compared with their contralateral developing limb so as to determine the similarities and differences in ectodermal-mesenchymal ultrastructural relationships in these systems. Prior to stage 53, mesenchymal cells in regenerating limbs, as well as mesenchyme cells in developing limbs appear undifferentiated; the cells are not visibly different. However, at stage 54 muscle and cartilage differentiation in the developing foot is distinct. Furthermore, in all larvae with regenerates at stages 50 to 52 the basal lamina is not evident subjacent to the apical tip of the epithelium which covers the amputation surface. A distinct basal lamina is present, however, beneath the epidermis in all embryonic limbs examined, including the apical tip, as well as in regenerates of stages 53 to 55 tadpoles. Also, a greater apical accumulation of extracellular matrix (ECM) and organized collagen is observed among the mesenchymal cells in regenerates of stages 53 to 55 tadpoles, and among the mesenchyme cells in developing limbs of stages 50 to 55, compared with pre-stage 53 regenerates. In cases in which an embryonic limb bud is composed of relatively undifferentiated cells (stages 50 to 52), events following amputation result in the complete regeneration of a limb. However, when amputated embryonic limbs contain differentiating tissues, (e.g., muscle and cartilage) only selective tissues undergo regeneration resulting in malformed (heteromorphic) regenerates.(ABSTRACT TRUNCATED AT 250 WORDS)


[Base pair substitutions induced by Escherichia coli K-12 mutator gene prv].
Using the trpA system of Yanofsky, it is shown that the mutator gene prv of Escherichia coli K-12 induces transitions in both directions (A:T in equilibrium G:C), and not A:T leads to leads to C:G and C:G leads to A:T transversions. The prv1 mutation was found to be recessive in prv+/prv1 merodiploid.


Solvent tolerant marine bacterium Bacillus aquimaris secreting organic solvent stable alkaline cellulase.
The organic solvent tolerant bacteria with their physiological abilities to decontaminate the organic pollutants have potentials to secrete extracellular enzymes of commercial importance. Of the 19 marine bacterial isolates examined for their solvent tolerance at 10vol.% concentration, one had the significant tolerance and showed a relative growth yield of 86% for acetone, 71% for methanol, 52% for benzene, 35% for heptane, 24% for toluene and 19% for ethylacetate. The phylogenetic analysis of this strain using 16S rDNA sequence revealed 99% homology with Bacillus aquimaris. The cellulase enzyme secreted by this strain under normal conditions showed an optimum activity at pH 11 and 45°C. The enzyme did show functional stability even at higher pH (12) and temperature (75°C) with residual activity of 85% and 95% respectively. The enzyme activity in the presence of different additives were in the following order: Co(+2)>Fe(+2)>NaOCl(2)>CuSO(4)>KCl>NaCl. The enzyme stability in the presence of solvents at 20vol.% concentration was highest in benzene with 122% followed by methanol (85%), acetone (75%), toluene (73%) and heptane (42%). The pre-incubation of enzyme in ionic liquids such as 1-ethyl-3-methylimidazolium methanesulfonate and 1-ethyl-3-methylimidazolium bromide increased its activity to 150% and 155% respectively. The change in fatty acid profile with different solvents further elucidated the physiological adaptations of the strain to tolerate such extreme conditions.


Matrix-Mediated Delivery of Silver Nanoparticles for Prevention of Staphylococcus aureus and Pseudomonas aeruginosa Biofilm Formation in Chronic Rhinosinusitis.
Chronic rhinosinusitis (CRS) is a chronic health condition affecting the sinonasal cavity. CRS-associated mucosal inflammation leads to sinonasal epithelial cell death and epithelial cell barrier disruption, which may result in recurrent bacterial infections and biofilm formation. For patients who fail medical management and elect endoscopic sinus surgery for disease control, bacterial biofilm formation is particularly detrimental, as it reduces the efficacy of surgical intervention. Effective treatments that prevent biofilm formation in post-operative patients in CRS are currently limited. To address this unmet need, we report the controlled release of silver nanoparticles (AgNps) with silk-elastinlike protein-based polymers (SELPs) to prevent bacterial biofilm formation in CRS. This polymeric network is liquid at room temperature and forms a hydrogel at body temperature, and is hence, capable of conforming to the sinonasal cavity upon administration. SELP hydrogels demonstrated sustained AgNp and silver ion release for the studied period of three days, potent in vitro antibacterial activity against Pseudomonas aeruginosa (**** p < 0.0001) and Staphylococcus aureus (**** p < 0.0001), two of the most commonly virulent bacterial strains observed in patients with post-operative CRS, and high cytocompatibility with human nasal epithelial cells. Antibacterial controlled release platform shows promise for treating patients suffering from prolonged sinonasal cavity infections due to biofilms.


In vivo pharmacological manipulation of small conductance Ca(2+)-activated K(+) channels influences motor behavior, object memory and fear conditioning.
Small conductance Ca(2+)-activated K(+) channels (SK, K(Ca2.1), K(Ca2.2), K(Ca2.3)) are expressed at high levels in brain regions critical for learning and memory. The activation of dendritic SK channels limits the induction of synaptic plasticity that may underlie hippocampal and amygdala dependent memory. EBIO facilitates SK channel activation by increasing their sensitivity to calcium. The compound CyPPA selectively activates SK2 and SK3 channels in a similar manner. To date there has been no report of the effects of SK channel activators on memory. Therefore, the present study examined the effects of systemic EBIO on mice in a behavioral task battery. Significant effects of EBIO on memory and motor activity were validated and extended by examining the effects of systemic CyPPA. Systemic EBIO and CyPPA both produced a transient decline in locomotor behavior. Neither SK channel activator affected anxiety. EBIO (17.5 mg/kg) impaired the encoding, but not retrieval, of object memory in a spontaneous object recognition task. A similar impairment of object memory encoding was observed in CyPPA (15 mg/kg)-treated mice. These memory-impairing effects were not due to changes in motivation, attention or movement. Systemic EBIO did not affect contextual or cued fear memory after conditioning with a 3 tone (CS)-footshock (US) pairing protocol or a 1 CS-US pairing protocol. Interestingly, apamin (0.4 mg/kg) enhanced contextual fear memory in mice conditioned with a 1 CS-US pairing protocol. These results suggest that SK channel activation impairs the encoding of non-aversive memory but not memory for aversive events. These data support converging evidence that SK channels regulate cellular mechanisms of memory encoding.


Value of fat suppression in gadolinium-enhanced magnetic resonance neuroimaging.
T1-weighted, gadolinium-enhanced magnetic resonance imaging is frequently used to investigate neurologic disease in small animals; however, the abundance of hyperintense adipose tissue adjacent to neural structures, particularly the cranial nerves and spinal cord, can decrease the conspicuity of contrast-enhanced tissues on T1-weighted images. For this reason, chemical fat saturation techniques are used to suppress the signal of adipose tissues, enabling improved depiction of gadolinium-enhanced structures and detection of lesions affecting the nervous system.


Posttransplant Outcomes for cPRA-100% Recipients Under the New Kidney Allocation System.
There is concern in the transplant community that outcomes for the most highly sensitized recipients might be poor under Kidney Allocation System (KAS) high prioritization. To study this, we compared posttransplant outcomes of 525 pre-KAS (December 4, 2009, to December 3, 2014) calculated panel-reactive antibodies (cPRA)-100% recipients to 3026 post-KAS (December 4, 2014, to December 3, 2017) cPRA-100% recipients using SRTR data. We compared mortality and death-censored graft survival using Cox regression, acute rejection, and delayed graft function (DGF) using logistic regression, and length of stay (LOS) using negative binomial regression. Compared with pre-KAS recipients, post-KAS recipients were allocated kidneys with lower Kidney Donor Profile Index (median 30% versus 35%, P < 0.001) but longer cold ischemic time (CIT) (median 21.0 h versus 18.6 h, P < 0.001). Compared with pre-KAS cPRA-100% recipients, those post-KAS had higher 3-year patient survival (93.6% versus 91.4%, P = 0.04) and 3-year death-censored graft survival (93.7% versus 90.6%, P = 0.005). The incidence of DGF (29.3% versus 29.2%, P = 0.9), acute rejection (11.2% versus 11.7%, P = 0.8), and median LOS (5 d versus 5d, P = 0.2) were similar between pre-KAS and post-KAS recipients. After accounting for secular trends and adjusting for recipient characteristics, post-KAS recipients had no difference in mortality (adjusted hazard ratio [aHR]: 0.861.623.06, P = 0.1), death-censored graft failure (aHR: 0.521.001.91, P > 0.9), DGF (adjusted odds ratio [aOR]: 0.580.861.27, P = 0.4), acute rejection (aOR: 0.610.941.43, P = 0.8), and LOS (adjusted LOS ratio: 0.981.161.36, P = 0.08). We did not find any statistically significant worsening of outcomes for cPRA-100% recipients under KAS, although longer-term monitoring of posttransplant mortality is warranted.


Ethics and informed consent for comparative effectiveness research with prospective electronic clinical data.
Electronic clinical data (ECD) will increasingly serve as an important source of information for comparative effectiveness research (CER). Although many retrospective studies have relied on ECD, new study designs propose using ECD for prospective CER. These designs have great potential but they also raise important ethics questions. Drawing on an ethics framework for learning health care systems, we identify morally relevant features of prospective CER-ECD studies by examining 1 case of an observational study and a second of a pragmatic, randomized trial. We focus only on questions of consent and assume research has been subject to appropriate ethics review and oversight. We conclude that a CER-ECD observational study that imposes no or minimal additional risk to or burden on patients may proceed ethically without express informed consent from participants in settings where: (a) patients are regularly informed of the health care institution's commitment to learning through the integration of research and practice; and (b) there are appropriate protections for patients' rights and interests. In addition, where (a) and (b) apply, some pragmatic, randomized trials that similarly impose no or minimal additional risk to or burden on patients may also proceed ethically without express consent, when certain additional conditions are satisfied, including: (c) the trial does not negatively affect patients' prospects for good clinical outcomes; (d) physicians have the option of using an intervention other than the one assigned if they believe doing so is important for a particular patient; and (e) the trial does not engage preferences or values that are meaningful to patients.


Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis.
γ-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.


Hydrogen sulfide mediates the anti-survival effect of sulforaphane on human prostate cancer cells.
Hydrogen sulfide (H(2)S) is a novel gasotransmitter that regulates cell proliferation and other cellular functions. Sulforaphane (SFN) is a sulfur-containing compound that exhibits anticancer properties, and young sprouts of broccoli are particularly rich in SFN. There is consistent epidemiological evidence that the consumption of sulfur-containing vegetables, such as garlic and cruciferous vegetables, may help reduce the occurrence of prostate cancer. Here we found that a large amount of H(2)S is released when SFN is added into cell culture medium or mixed with mouse liver homogenates, respectively. Both SFN and NaHS (a H(2)S donor) decreased the viability of PC-3 cells (a human prostate cancer cell line) in a dose-dependent manner, and supplement of methemoglobin or oxidized glutathione (two H(2)S scavengers) reversed SFN-reduced cell viability. We further found both cystathionine gamma-lyase (CSE) and cystathionine beta-synthase are expressed in PC-3 cells and mouse prostate tissues. H(2)S production in prostate tissues from CSE knockout mice was only 20% of that from wild-type mice, suggesting CSE is a major H(2)S-producing enzyme in prostate. CSE overexpression enhanced H(2)S production and inhibited cell viability in PC-3 cells. In addition, both SFN and NaHS activated p38 mitogen-activated protein kinases (MAPK) and c-Jun N-terminal kinase (JNK). Pre-treatment of PC-3 cells with methemoglobin decreased SFN-stimulated MAPK activities. Suppression of both p38 MAPK and JNK reversed H(2)S- or SFN-reduced viability of PC-3 cells. Our results demonstrated that H(2)S mediates the inhibitory effect of SFN on the proliferation of PC-3 cells, which suggests that H(2)S-releasing diet or drug might be beneficial in the treatment of prostate cancer.


The usefulness of the likelihood ratio in the diagnosis of dyspepsia and gastroesophageal reflux disease.
Clinicians are familiar with the concepts of sensitivity and specificity to describe the accuracy of a diagnostic test. These measures do not always express the probability that a patient has a disease with a given test result as this will vary with the prevalence of the disorder in the population. The likelihood ratio is a more clinically relevant method of reporting accuracy, and the probability of having a disease after a positive or negative test can be calculated. The likelihood ratio can be applied to the clinical problem of dyspepsia management. This suggests that Helicobacter pylori (H. pylori) test and treat will detect and treat most peptic ulcers with only 0.5% of H. pylori-negative patients having peptic ulcer disease. Serology is possibly acceptable in populations with an H. pylori prevalence of approximately 50%. The urea breath tests are more appropriate in more extreme prevalence ranges. Once the prevalence of H. pylori falls below 10%, then the urea breath test becomes inaccurate, and screening and treatment may be less appropriate. The absolute probability of having peptic ulcer disease in a largely H. pylori-negative population will be very small, however, and the appropriateness of performing any investigation in these circumstances is debatable. Finally, likelihood ratios indicate that the clinical diagnosis of gastroesophageal reflux disease (GERD) is not straightforward. Traditionally, it is believed that patients with dominant heartburn are likely to have GERD. Likelihood ratios predict, however, that patients with these symptoms have a little over 50% chance of having GERD as defined by 24-h esophageal pH studies.


[A monoclonal antibody against ragweed pollen cross-reacting with yellow dock pollen].
Using monoclonal antibodies with different specificity against the major allergenic components of ragweed pollen, we analyzed their cross-reactivity with two tree pollens, two grass pollens and five other weed pollens which are common in Taiwan by the immunoblot method. It was found that besides reacting with AgE and AgK of the ragweed pollen, the monoclonal antibody 48-5 also reacted with antigens of yellow dock pollen with molecular weights of 40K, 38K, 24K, and 21K. In a preliminary study, sera of two patients containing IgE antibodies to ragweed pollen antigens also reacted to the 40K component of the yellow dock pollen. Furthermore, from the results of allergenic skin testings on 109 patients with bronchial asthma, we found that of 22 patients who had a positive reaction to a crude extract of ragweed pollen, 18(81.8%) also reacted to the crude extract of yellow dock pollen. In conclusion, our results suggest that there exists a common allergenic determinant between pollens of ragweed and yellow dock. It may play an important role in the expression of the sensitivity of patients to these two kinds of pollens.


Fructose and prostate cancer: toward an integrated view of cancer cell metabolism.
Activation of glucose transporter-1 (Glut-1) gene expression is a molecular feature of cancer cells that increases glucose uptake and metabolism. Increased glucose uptake is the basis for the clinical localization of primary tumors using positron emission tomography (PET) and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) as a radiotracer. However, previous studies have demonstrated that a considerable number of cancers, which include prostate cancer (CaP), express low to undetectable levels of Glut-1 and that FDG-PET has limited clinical applicability in CaP. This observation could be explained by a low metabolic activity of CaP cells that may be overcome using different hexoses, such as fructose, as the preferred energy source. However, these hypotheses have not been examined critically in CaP. This review article summarizes what is currently known about transport and metabolism of hexoses, and more specifically fructose, in CaP and provides experimental evidences indicating that CaP cells may have increased capacity to transport and metabolize fructose in vitro and in vivo. Moreover, this review highlights recent findings that allow better understanding of how metabolism of fructose may regulate cancer cell proliferation and how fructose uptake and metabolism, through the de novo lipogenesis pathway, may provide new opportunities for CaP early diagnosis, staging, and treatment.